US4994463A - Tricyclic thromboxane A2 antagonists - Google Patents

Tricyclic thromboxane A2 antagonists Download PDF

Info

Publication number
US4994463A
US4994463A US07/281,545 US28154588A US4994463A US 4994463 A US4994463 A US 4994463A US 28154588 A US28154588 A US 28154588A US 4994463 A US4994463 A US 4994463A
Authority
US
United States
Prior art keywords
sub
compound
oxepin
dihydrodibenz
piperazinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
US07/281,545
Other languages
English (en)
Inventor
Etsuo Oshima
Hiroyuki Obase
Akira Karasawa
Kazuhiro Kubo
Ichiro Miki
Akio Ishii
Hidee Ishii
Kenji Ohmori
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
KH Neochem Co Ltd
Original Assignee
Kyowa Hakko Kogyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kyowa Hakko Kogyo Co Ltd filed Critical Kyowa Hakko Kogyo Co Ltd
Assigned to KYOWA HAKKO KOGYO CO., LTD., A CORP. OF JAPAN reassignment KYOWA HAKKO KOGYO CO., LTD., A CORP. OF JAPAN ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: ISHII, AKIO, ISHII, HIDEE, KARASAWA, AKIRA, KUBO, KAZUHIRO, MIKI, ICHIRO, OBASE, HIROYUKI, OHMORI, KENJI, OSHIMA, ETSUO
Application granted granted Critical
Publication of US4994463A publication Critical patent/US4994463A/en
Priority to US07/884,208 priority Critical patent/US5302602A/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
    • C07D313/12—[b,e]-condensed
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel tricyclic compounds which strongly antagonize an action of thromboxane A 2 (hereafter referred to as TXA 2 ) and possess an antiallergic and/or antihistaminic activity.
  • TXA 2 strongly aggregates platelets and is a potent vasoconstrictor [cf. Arachidonic Acid Cascade and Drugs, edited by Shozo Yamamoto, Gendai Iryo Publishing Co., Ltd. (1985)]. Further TXA 2 is a powerful vasoconstrictor against bronchus and bronchial smooth muscle. Therefore, TXA 2 is considered to take part in pathological conditions over a wide range. As examples, the following diseases can be exemplified.
  • myocardial infarction for example, myocardial infarction, angina pectoris, and thrombosis
  • transient ischemic attack migraine, cerebral hemorrhage, and cerebral infarction
  • Atherosclerosis For example, atherosclerosis, capillary convulsion, peripheral circulation disorders, hypertension, and pulmonary embolism
  • bronchial asthma for example, bronchial asthma, bronchitis, pneumonia, nephritis, and hepatitis
  • compounds that antagonize the action of TXA 2 are expected to have therapeutic effects in preventing or treating one or more of the diseases described above or other diseases involving TXA 2 . Furthermore, in those instances where use of a particular drug was limited due to side effects mediated by TXA 2 or considered to be mediated by TXA 2 , it is expected to alleviate the side effects by the use of compounds which antagonize the action of TXA 2 .
  • TXA 2 is also thought to play a role in the pathogenesis of allergic diseases, especially of an asthma [cf. J. Allergy Clin. Immunol., 77, 122 (1986); Arch. Pharmacol., 327, 148 (1984)].
  • TXA 2 As an antagonist of TXA 2 , representative compounds are exemplified in Thrombosis Research, 44, 377 (1986).
  • an indole compound having the following structure: ##STR2## and the like are disclosed in Japanese Published Unexamined Patent Application No. 249960/1986 [West German Patent Application (DE) No. 3,514,696] and a compound having the following structure: ##STR3## and the like are disclosed in Japanese Published Unexamined Patent Application No. 212552/1986 [West German Patent Application (DE) No. 3,508,692]. These compounds have a phenylsulfonamide group as a side chain and exhibit an activity of antagonizing TXA 2 .
  • R o as a substituent on the aromatic ring has carboxyl or a derivative thereof (for example, an ester, an amide, etc.; hereafter collectively referred to as carboxylic acid group) directly or via an alkylene chain, etc. and W o is hydrogen or a substituent such as oxo ( ⁇ O), methylene ( ⁇ CH 2 ), hydroxyl, alkoxyl, etc., oxepine derivatives wherein X 1 -X 2 is --CH 2 O-- are known as showing antiinflammatory or antiallergic activities, etc. [J. Med.
  • oxepine derivatives wherein R o is hydrogen or a substituent other than the carboxylic acid group, such as, alkyl, alkoxyl, halogen, etc. and W o has a (di)alkylaminoalkyl chain via --S-- show antiasthmatic activities [Japanese Published Unexamined Patent Application No. 126883/1983 (EP 0085870A)]. It is also known that derivatives such as oxepine or thiepine (wherein X 1 -X 2 is --CH 2 S--) wherein W o is alkylaminoalkylidene show an antidepressant action, etc. [U.S. Pat. Nos.
  • oxepine or cycloheptene (wherein X 1 -X 2 is --CH 2 CH 2 --) derivatives showing an antihistaminic activity wherein W o is a (di)alkylaminoalkylidene are known [Japanese Published Unexamined Patent Application No. 45557/1986 (EP 214779A)].
  • oxepine derivatives wherein W o is an alkylidene substituted with an alicyclic nitrogen-containing heterocyclic group such as 4-methylpiperazinyl, 4-methylhomopiperazinyl, piperidino, pyrrolidinyl, thiomorpholino or morpholino or with a (di)alkyl-substituted amino at the terminal thereof are known as showing an antiallergic and antiinflammatory activity [Japanese Published Unexamined Patent Application No. 10784/1988 (EP 0235796A)].
  • Novel and useful TXA 2 antagonists are expected to have preventive and therapeutic effects on various diseases, and are in demand. Further antiallergic agents having a TXA 2 -antagonizing activity are expected to have preventive and therapeutic effects on allergic diseases, and are in demand.
  • An object of the present invention is to provide novel tricyclic compounds having a TXA 2 -antagonizing activity and antiallergic activity by containing both a carboxylic acid group as the foresaid R o , and, as the aforesaid W o , an alkylthio chain or alkylidene chain substituted at the terminal thereof with an alicyclic nitrogen-containing heterocyclic group having a substituent such as aryl, aralkyl, etc. thereon.
  • the present invention relates to a tricyclic compound [hereafter referred to as Compound (I); compounds having other formula numbers are also the same] represented by formula (I): ##STR5## wherein represents single bond or double bond;
  • X 1 -X 2 represents --CH 2 O--, ##STR6## wherein l represents 0, 1 or 2, --CH 2 --CH 2 --, or --CH ⁇ CH--;
  • W represents --S-- or ⁇ CH--
  • n 1, 2, 3, or 4;
  • R A and R B represents hydrogen and the other represents --Y--M wherein Y represents single bond, --CR 1 R 2 --(CH) m --, or --CR 1 ⁇ CR 2 --(CH 2 ) m -- wherein each of R 1 and R 2 independently represents hydrogen or lower alkyl and m is 0, 1, 2, 3 or 4, in which the left side of each formula is bound to the mother nucleus; and M represents --COOR 3 wherein R 3 represents hydrogen or lower alkyl, --CONR 3a R 3b wherein each of R 3a and R 3b independently has the same significances for R 3 as described above, or tetrazolyl;
  • each of G A and G B independently represents lower alkyl, halogen, hydroxyl, or lower alkoxyl;
  • each of g A and g B independently represents 0, 1, 2 or 3;
  • Z represents >N--E 1 --Q wherein E 1 represents single bond, --CO--, --COO-- wherein the left side of the formula is bound to the nitrogen atom, or --SO 2 --; and Q represents optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, aromatic heterocyclic group, or ##STR7## wherein L represents hydrogen, hydroxyl, or lower alkoxy; E 2 represents single bond, --CO--, or ##STR8## wherein R 4 represents hydrogen or lower alkyl; and Q has the same significance as described above; >C ⁇ CH--Q wherein Q has the same significance as described above; or ##STR9## p is 1, 2 or 3; and a pharmaceutically acceptable salt thereof.
  • the aryl is exemplified by phenyl and naphthyl having 6 to 10 carbon atoms, etc.
  • the aralkyl is exemplified by benzyl, phenethyl, benzhydryl and trityl, etc. having 7 to 20 carbon atoms, etc.
  • the aralkenyl is exemplified by styryl and cinnamyl having 8 to 18 carbon atoms, etc.
  • each group means independently 1 to 3 substituents on the aromatic ring and includes a group selected from lower alkyl, halogen, trifluoromethyl, hydroxyl, lower alkoxyl and methylenedioxy formed together with the ortho-position thereof.
  • the aromatic heterocyclic group shown by Q represents a group selected from furyl, thienyl, pyridyl, pyrimidinyl, quinolyl and isoquinolyl.
  • the alkyl moiety in the lower alkyl and lower alkoxyl is a straight or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, etc.;
  • the halogen includes, for example, fluorine, chlorine, bromine and iodine.
  • the pharmaceutically acceptable salt of Compound (I) includes an acid addition salt, a metal salt, an ammonium salt, an organic amine addition salt, an amino acid addition salt, etc. which are pharmaceutically acceptable.
  • the pharmaceutically acceptable acid addition salt of Compound (I) mention may be made of the inorganic acid salt such as hydrochloride, sulfate, phosphate, etc. and the organic acid salt such as acetate, malate, fumarate, tartarate, citrate, etc.
  • the pharmaceutically acceptable metal salt the alkali metal salt such as sodium salt, potassium salt, etc.; alkaline earth metal salt such as magnesium salt, calcium salt, etc. and further the aluminum salt and the zinc salt are appropriate.
  • the ammonium salt mention may be made of the salt of ammonium, tetramethylammonium, etc.
  • the pharmaceutically acceptable organic amine addition salt mention may be made of an addition salt of morpholine, piperidine, etc.
  • the pharmaceutically acceptable amino acid addition salt an addition salt of lysine, glycine, phenylalanine and the like are mentioned.
  • the reaction solvent may be chosen from water or an organic solvent which does not participate in the reaction and can be used alone or in combination.
  • the organic solvent includes, for example, an alcohol such as methanol, ethanol, propanol, isopropanol, etc.; an ether such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, etc.; a hydrocarbon such as benzene, toluene, xylene, hexane, cyclohexane, petroleum ether, ligroin, decalin, etc.; a ketone such as acetone, methyl ethyl ketone, etc.
  • an amide such as formamide, dimethylformamide, hexamethylphosphoric triamide, etc.; acetonitrile, ethyl acetate, dimethylsulfoxide, sulfolane or a halogenated hydrocarbon such as methylene chloride, dichloroethane, tetrachloroethane, chloroform or carbon tetrachloride, etc.
  • bases or acids later described are liquid, they may also be used as a solvent.
  • an inorganic or organic base can be used.
  • bases include an alkali metal hydroxide, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate, for example, sodium carbonate, sodium hydrogencarbonate or potassium carbonate; an alkali metal acetate, for example, sodium acetate or potassium acetate; an alkali metal alkoxide, for example, sodium methoxide, sodium ethoxide or potassium tert-butoxide; or an organic metal compound, for example, sodium hydride, n-butyl lithium, sec-butyl lithium; and an organic amine, for example, triethylamine, tri-n-butylamine, pyridine, N,N-dimethylaminopyridine, picoline, lutidine, N,N-dimethylaniline, dicyclohexylmethylamine, N-methylpiperidine, morpholine, diazabicyclooctane, diazabicyclo
  • an inorganic or organic acid or Lewis acid can be used as the appropriate acid.
  • the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, hypochloric acid, sulfurous acid or nitrous acid, etc.
  • the organic acid include formic acid, acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid or methanesulfonic acid, etc.
  • the Lewis acid include aluminum chloride, zinc chloride, tin chloride, boron trifluoride, boron trifluoride diethyl ether complex, titanium tetrachloride, etc.
  • the reaction temperature is generally from -80° C. to a boiling point of a solvent. Heating without a solvent is also possible.
  • the reaction may generally be carried out under normal pressure but it is also possible to apply pressure. In this case, the reaction temperature may be raised to a temperature higher than the boiling point of a solvent.
  • the reaction time is generally in a range of one minute to one week.
  • Compound (I) can be prepared from Compound (II) or from Compounds (IIIa through d), etc. obtained from Compound (II) according to the following reaction steps: ##STR12## wherein ##STR13## has the same significance as described above; R 5 represents lower alkyl, Hal represents halogen and Ph represents phenyl.
  • Hal represents chlorine, bromine and iodine and the lower alkyl has the same significance as defined for the lower alkyl in each group in formula (I).
  • Compounds (IIIa to d) can be synthesized from Compound (II) according to methods described in Japanese Published Unexamined Patent Application Nos. 150083/1981; 28972/1985; 152670/1986; 152671/1986; 152672/1986; 152675/1986 and 10784/1988, etc. or in a manner similar thereto.
  • Compound (Ia) can be obtained from Compounds (IIIa to c) and (IVa) according to the following reaction step: ##STR15## wherein A 1 represents OH, OR 5 or Hal; and ##STR16## Z, R 5 , Hal and p have the same significances as described above.
  • Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of an appropriate dehydration condensing agent, for example, trifluoroacetic anhydride at from 0° C. to room temperature for 1 to 24 hours in an inert solvent such as methylene chloride, chloroform, etc., then adding 1 to 5 molar equivalents of Compound (IVa) or acid addition salts thereof (for example, hydrochloride, hydrobromide, acetate, trifluoroacetate, p-toluenesulfonate, etc.; the same is applied hereafter) to the reaction solution and carrying out the reaction at 0° C. to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex.
  • an appropriate dehydration condensing agent for example, trifluoroacetic anhydride
  • Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIb) with 1 to 5 molar equivalents of Compound (IVa) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, etc., at 0° C. to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex.
  • an inert solvent such as methylene chloride, chloroform, etc.
  • Compound (Ia) or acid addition salts thereof can be obtained by reacting Compound (IIIc) with 1 to 10 molar equivalents of Compound (IVa) or acid addition salts thereof in an inert solvent such as methylene chloride, chloroform, dimethylformamide, etc., at 0° C. to a boiling point of the solvent for 1 to 24 hours, if necessary, in the presence of a base such as triethylamine, sodium hydride, etc.
  • an inert solvent such as methylene chloride, chloroform, dimethylformamide, etc.
  • Compound (Ia) can be obtained from Compounds (IIIa-c) according to the following reaction steps.
  • Compound (VIb) or (VIc) is prepared from Compounds (IIIa-c) according to the following reaction steps: ##STR17## wherein ##STR18## A 1 , Hal and n have the same significances as described above; and R 6 represents a group capable of being split as OR 6 .
  • R 6 means, for example, alkylsulfonyl such as methanesulfonyl, trifluoromethanesulfonyl, etc. and arylsulfonyl such as phenylsulfonyl, p-toluenesulfonyl, etc.
  • the corresponding Compound (VIa) or (VIc) can be obtained by reacting Compound (IIIa) with 1 to 5 molar equivalents of an appropriate dehydrating and condensing agent, for example, trifluoroacetic anhydride, in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of from 0° C.
  • an appropriate dehydrating and condensing agent for example, trifluoroacetic anhydride
  • Compound (VIa) or (VIc) can also be obtained by reacting Compound (IIIb) or (IIIc) with 1 to 10 molar equivalents of an alcohol (Va) or its halide (Vb) in an inert solvent such as methylene chloride, chloroform, etc., at a temperature of between room temperature and the boiling point of the solvent, if necessary and desired, in the presence of an appropriate acid catalyst, for example, boron trifluoride diethyl ether complex, or an appropriate base such as triethylamine for 1 to 24 hours.
  • an appropriate acid catalyst for example, boron trifluoride diethyl ether complex, or an appropriate base such as triethylamine for 1 to 24 hours.
  • Compound (VIa) may be reacted with 1 to 5 molar equivalents of Hal-R 6 or (R 6 ) 2 O (wherein R 6 and Hal have the same significances as described above) in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from -50° C. to room temperature for 1 to 24 hours to give Compound (VIb).
  • an inert solvent such as methylene chloride, chloroform, etc.
  • compound (VIa) may be reacted (1) with 1 to 5 molar equivalents of a halogenating agent, for example, thionyl chloride, in an inert solvent such as methylene chloride, chloroform, etc., if necessary and desired, in the presence of a base such as pyridine, etc., at a temperature of from 0° C.
  • a halogenating agent for example, thionyl chloride
  • Compound (VIc) is the chloride (Hal is Cl) or bromide (Hal is Br)
  • the compound may be reacted further with an iodide, for example, sodium iodide, in a polar solvent such as acetonitrile to give the iodide (Hal is I).
  • Compound (VIb) can be converted into Compound (VIc) under similar conditions.
  • Compound (VIb) or (VIc) can be converted into Compound (Ia) according to the following reaction step: ##STR19## wherein A 2 represents OR 6 or Hal; and R 6 , Hal, ##STR20## Z, p and n have the same significances as described above.
  • Compound (Ia) can be obtained by reacting Compound (VIb) or Compound (VIc) with 1 to 10 molar equivalents of Compound (VII), if necessary, in the presence of a molar equivalent to a largely excessive amount of a base such as sodium carbonate, triethylamine, pyridine, Triton B, sodium hydride, etc., at a temperature of between room temperature and the boiling point of the solvent for 1 to 48 hours in an inert solvent such as methylene chloride, chloroform, dichloroethane, dimethylformamide, dioxane, etc.
  • a base such as sodium carbonate, triethylamine, pyridine, Triton B, sodium hydride, etc.
  • reaction of Compound (VIc) with Compound (VII) may also be carried out in the presence of an iodide, for example, sodium iodide or potassium iodide.
  • an iodide for example, sodium iodide or potassium iodide.
  • Compound (Ib) can be prepared according to the following reaction steps: ##STR22## wherein ##STR23## Z, Ph, n and p have the same significance as described above.
  • a base such as n-butyl lithium, etc.
  • an inert solvent for example, tetrahydrofuran, etc.
  • Compound (Ib) can be obtained by reacting 1 to 5 molar equivalents, based on Compound (II), of Compound (VIIIa), after or without isolation, with Compound (II) in an inert solvent, for example, tetrahydrofuran, etc., at a temperature of from 0° C. and a boiling point of the solvent.
  • an inert solvent for example, tetrahydrofuran, etc.
  • Compound (Ib) can also be obtained from Compound (II) according to the following reaction steps: ##STR26## wherein ##STR27## Z, Hal, n and p have the same significances as described above.
  • Compound (IVc) can be obtained by reacting corresponding Compound (IVb) with 0.5 to 2 molar equivalents of magnesium in an inert solvent such as tetrahydrofuran, diethyl ether, etc., if necessary and desired, in the presence of a trace amount of iodine, at a temperature of from 0° C. to a boiling point of the solvent for 0.5 to 12 hours.
  • an inert solvent such as tetrahydrofuran, diethyl ether, etc.
  • Compound (IX) can be subjected to dehydration to give Compound (Ib).
  • hydroxyl-protecting group groups generally used as protective groups for an alcoholic hydroxyl may be used.
  • a preferred protecting agent is, for example, tetrahydropyranyl or the like.
  • an ylide (VIIIc) in which hydroxyl is protected by an appropriate protective group for example, tetrahydropyranyl, etc.
  • an inert solvent for example, tetrahydrofuran
  • Compound (Xa) can be converted into Compound (Xb) by removing the protective group.
  • the removal of protective group can be conducted in a conventional manner; in the case of using, for example, tetrahydropyranyl as a protective group, Compound (Xa) is treated with an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc. in a suitable hydrated solvent such as hydrated dioxane, hydrated tetrahydrofuran, etc., at a temperature of from 0° C. to the boiling point of the solvent for 1 to 24 hours to give Compound (Xb).
  • an acid catalyst such as p-toluenesulfonic acid, hydrochloric acid, etc.
  • a suitable hydrated solvent such as hydrated dioxane, hydrated tetrahydrofuran, etc.
  • Compound (Xb) can be led to Compound (Ib) via Compound (Xc) or Compound (Xd) by the following reaction steps: ##STR30## wherein ##STR31## Z, R 6 , Hal, n and p have the same significances as described above.
  • the reactions can be performed in a manner similar to the method for leading from Compound (VIa) to Compound (Ia) described in Method 1-2.
  • Compound (Ib-1) can be prepared according to the following reaction steps: ##STR33## wherein ##STR34## Z, R 6 , Hal and p have the same significances as described above; [CH 2 O] represents formaldehyde and/or a polymer thereof; R 8a and R 8b , which may be the same or different, each represents lower alkyl or may be combined to nitrogen adjacent thereto to form a heterocyclic ring and R 9 represents lower alkyl.
  • the lower alkyl in the definitions of R 8a , R 8b and R 9 has the same significance as described for the lower alkyl in formula (I).
  • the heterocyclic ring formed by R 8a and R 8b mention may be made of pyrrolidine, piperidine, N-methylpiperazine, morpholine, thiomorpholine, N-methylhomopiperazine and the like.
  • Compound (IIId) is reacted with 1 to 10 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, either in a hydrohalogenic acid, preferably hydrochloric acid or in an inert solvent, for example, dioxane, saturated with hydrogen chloride and, if necessary and desired, in the presence of a strong acid such as sulfuric acid or trifluoroacetic acid, at a temperature of from room temperature to the boiling point of the solvent, for 1 to 24 hours to give Compound (Xd-1).
  • a hydrohalogenic acid preferably hydrochloric acid or in an inert solvent, for example, dioxane
  • an inert solvent for example, dioxane
  • a strong acid such as sulfuric acid or trifluoroacetic acid
  • Compound (Xd-1) can also be obtained as follows. That is, Compound (IIId) is reacted with 1 to 2 molar equivalents of formaldehyde and/or a formaldehyde polymer, for example, paraformaldehyde, and 1 to 3 molar equivalents of a secondary amine (XI) and trifluoroacetic acid, in an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc., if necessary and desired, in the presence of acetic acid, at a temperature of from room temperature to the boiling point of the solvent, for 1 to 48 hours to give Compound (Xe) or acid addition salts thereof.
  • an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc.
  • Compound (Xe) can be led to Compound (Xd-1) by reacting with 1 to 10 molar equivalents of a halocarbonate, preferably ethyl chloroformate in an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc., if necessary, in the presence of the base such as triethyl amine and sodium acetate between at 0° C. and the boiling point of the solvent for 1 to 48 hours.
  • a halocarbonate preferably ethyl chloroformate
  • an inert solvent such as methylene chloride, chloroform, dichloroethane, tetrachloroethane, etc.
  • Compound (Ib-1) can also be obtained according to the method for obtaining Compound (Xe) from Compound (IIId) in which Compound (VII) is used in place of Compound (XI).
  • Compound (Ic) can be prepared from Compounds (XII) and (XIII) obtained in a manner similar to Methods 1 and 2 described above by the following reaction steps: ##STR36## wherein W, E 1 , Q, n and p have the same significances as described above and A 3 represents a leaving group in --E 1 --Q.
  • leaving group A 3 represents halogen such as chlorine, bromine, iodine, etc. and in the case that E 1 is --CO--, A 3 --E 1 --Q represents HOOC--Q (A 3 is OH) or a carboxylic acid reactive derivative.
  • the carboxylic acid reactive derivative includes an acid halide (acid chloride, acid bromide, etc.), an acid anhydride (acid anhydride formed with a dehydrating condensing agent such as N,N'-dicyclohexylcarbodiimide, etc., in the reaction system, commercially available acid anhydrides, etc.), an activated ester (p-nitrophenyl ester, N-hydroxysuccinimide ester, etc.), a mixed acid anhydride (monoethyl carbonate, monoisobutyl carbonate, etc.) and the like.
  • E 1 is --COO--
  • a 3 represents halogen as described above and in the case that E 1 is --SO 2 --, A 3 represents halogen or --O--SO 2 --Q.
  • Compound (Ic) can be obtained by reacting Compound (XII) or acid addition salts thereof with 1 to 5 molar equivalents of Compound (XIII), either in an inert solvent such as methylene chloride, chloroform, etc., in the presence of a base such as pyridine, etc., or in a basic organic solvent such as pyridine or triethylamine, etc., at a temperature of 0° C. to room temperature for 1 to 24 hours.
  • an inert solvent such as methylene chloride, chloroform, etc.
  • a base such as pyridine, etc.
  • a basic organic solvent such as pyridine or triethylamine, etc.
  • Compound (Id) can be obtained by hydrolysis of the corresponding carboxylic acid ester.
  • Compound (Id) can be obtained by subjecting Compound (Ie) [in Compound (I), compound wherein M is --COOR 3 c (wherein R 3c represents lower alkyl in the definitions for R 3 described above)] synthesized according to Methods 1 to 3, to an appropriate hydrolysis method, for example, by reacting with a molar equivalent to an excess of sodium hydroxide or potassium hydroxide, etc. in a solvent mixture of a lower alcohol such as methanol, ethanol, etc. and water, at a temperature of from room temperature to the boiling point of the solvent for 1 to 48 hours.
  • a solvent mixture of a lower alcohol such as methanol, ethanol, etc. and water
  • Compound (Id-1) can be obtained according to the following reaction steps: ##STR39## wherein one of Hal A and Hal B represents Hal and the other represents hydrogen; and , X 1 -X 2 , R A2 , R B2 , G A , G B , W, Z, Hal, n, g A , g B and p have the same significances as described above.
  • Compound (Id-1) can be obtained by carboxylating Compound (XIV) synthesized from Compound (II-1) in a manner similar to Methods 1 to 3.
  • Carboxylation can be performed by reacting, for example, Compound (XIV) with 1 molar equivalent of a metallizing agent, e.g., n-butyl lithium, in an inert solvent such as tetrahydrofuran, etc., at a temperature of from -78° C. to room temperature, for 10 minutes to 12 hours followed by reacting the resulting reaction mixture with 1 molar equivalent to a largely excessive amount of carbon dioxide at a temperature of from -78° C. to room temperature, for 10 minutes to 12 hours.
  • Compound (Id-1) can be obtained by preparing the corresponding Grignard reagent from Compound (XIV) and magnesium in an inert solvent such as diethyl ether, etc. in a manner similar to Method 2-2 and reacting the reagent with carbon dioxide, and the like method.
  • the groups may be subjected to conventional means used in organic synthesis chemistry, for example, means for protecting functional groups, means for removing protection, etc. [for example, cf., Green, Protective Groups in Organic Synthesis, John Wiley & Sons Incorporated (1981)], methods for oxidation, reduction, hydrolysis, etc. [for example, cf., SHIN-JIKKEN KAGAKU KOZA, vols. 14 & 15, Maruzen (1977)].
  • group M is --COOH
  • 4,4-dimethyloxazoline, etc. are preferably used as a protecting group for --COOH (for example, Japanese Published Unexamined Patent Application No. 10784/1988) in the method in which the corresponding ester is hydrolyzed (cf. Method 4-1 described above) or in the reaction using a Grignard reagent (cf., for example, Method 2-2).
  • a desired compound can be obtained by hydrolyzing (removing a protecting group in) a compound obtained by Methods 1 through 4, etc.
  • group --Y--M is --Y'--CH 2 OR 10 [wherein Y' represents a group obtained by removing CH 2 from Y and R 10 represents a protecting group for hydroxyl (e.g., acetyl, tetrahydropyranyl, etc.)] to convert into --Y'-CH 2 OH and oxidizing the compound.
  • Y' represents a group obtained by removing CH 2 from Y and R 10 represents a protecting group for hydroxyl (e.g., acetyl, tetrahydropyranyl, etc.)] to convert into --Y'-CH 2 OH and oxidizing the compound.
  • the intermediates and objective compounds in the respective methods described above can be isolated and purified by purification methods conventionally used in organic synthesis chemistry, for example, filtration; extraction, washing, drying, concentration, recrystallization, various column chromatographies, etc. Further the intermediates may also be provided in the subsequent reaction, without being particularly purified.
  • E- and Z-forms may be isomerized from each other. This can be made by treating each isomer under reflux in, e.g., acetic acid, for 1 to 24 hours, in the presence of an appropriate acid catalyst such as p-toluenesulfonic acid, etc.
  • an appropriate acid catalyst such as p-toluenesulfonic acid, etc.
  • Compound (I) includes not only the E/Z isomers described above but also all possible stereoisomers and a mixture thereof.
  • the thus formed compound (I) may be purified as is.
  • salts may be formed in a conventional manner.
  • Compound (I) and pharmaceutically acceptable salts thereof may also be present in the form of addition products to water or various solvents; these adducts including the pharmaceutically acceptable salts are also included in the present invention.
  • Compounds (I) exhibit a potent TXA 2 antagonizing activity and some of them also possess an antiallergic activity and/or antihistaminic activity.
  • Preferred examples of Compound (I) are shown in Table 2.
  • TXA 2 antagonizing activity of Compound (I) is described below.
  • PCA passive cutaneous anaphylaxis
  • Anti-EWA rat serum was prepared according to the method of Stotland and Share [Can. J. Physiol. Pharmacol., 52, 1114 (1974)]. That is, 1 mg of EWA was mixed with 20 mg of aluminum hydroxide gel and 0.5 ml of pertussis-diphtheria-tetanus mixed vaccine. The mixture was subcutaneously administered to the rat paw in 4 portions. Fourteen days after, blood was collected from the carotid artery and the serum was isolated and stored in a state frozen at -80° C. Titer of this antiserum to homologous PCA for 48 hours was 1:32.
  • the case showing that the inhibition rate is 50% or more is judged to be positive in the PCA inhibition activity and the minimum dose in which at least one out of 3 rats was recognized to be positive was defined as the minimum effective dose (MED) of the test compound.
  • a test compound was orally (po; 300 mg/kg) or intraperitoneally (ip; 100 mg/kg) administered.
  • MLD the minimum lethal dose
  • Compound (I) and pharmaceutically acceptable salts thereof possess an excellent TXA 2 antagonizing activity and some compounds also possess an antiallergic activity.
  • Receptor binding was determined by a modified method of Kattelman et al. [Thrombosis Research, 41, 471 (1986)].
  • Compound (I) and pharmaceutically acceptable salts thereof have an excellent binding ability to TXA 2 receptor.
  • Receptor binding was determined by the method of chang et al. [J. Neurochem., 32, 1953 (1979)].
  • the cerebellum of guinea pig was suspended in a 40-fold mount (V/W) of chilled 50 mM phosphate buffer (pH 7.5) with Polytron Homogenizer (Kinematica Co., Ltd.). The suspension was centrifuged (35,500 ⁇ g, 10 minutes). The resulting precipitates were resuspended in an equal amount of fresh buffer followed by centrifugation. A 100-fold amount v/W) of chilled buffer was added to the final precipitates.
  • the amount bound in the presence of a test compound is an amount of 3 H-pyrilamine-bound radioactivity in the presence of a test compound in various concentrations.
  • Compound (I) and pharmaceutically acceptable salts thereof may be administered alone but in general, it is preferably administered as various medical preparation. These medical preparations are used for animal and human beings.
  • the medical preparation in accordance with the present invention may contain, as an active ingredient, Compound (I) or pharmaceutically acceptable salts thereof singly or as admixture with other optional effective components for different treatment. Further these medical preparations can be produced by optional procedures well known in the pharmaceutical field, by mixing the active ingredient together with one or more pharmaceutically acceptable carriers.
  • a steroid a non-steroid antiinflammatory agent, a peripheral analgesic, a leucotriene antagonist, a leucotriene biosynthesis inhibitor, an H 2 receptor antagonist, an antihistaminic agent, a histamine release inhibitor, a bronchodilator, an angiotensin converting enzyme inhibitor, a thromboxane A 2 biosynthesis inhibitor, an H + -K + ATPase inhibitor, a coronary dilator, a calcium antagonist, a diuretic, a xanthine oxidase inhibitor, a cerebral circulation improving agent, a celebral metabolism activator, a cerebral protecting agent, a liver protecting agent, an antiplatelet agent, a thrombolytic agent, an adrenaline ⁇ receptor antagonist, an adrenergic ⁇ receptor agent, an adrenaline ⁇ receptor antagonist, a seroton, a steroid, a non-steroid antiinflammatory agent, a peripheral analgesic, a leucotriene antagonist
  • the most effective route for treatment be selected as a route for administration.
  • Oral or parenteral administration such as intrarectal, topical, intranasal, intraocular, intrabuccal, subcutaneous, intramuscular and, intravenous routes, etc. are mentioned.
  • prepartions of the invention may be administered as a capsule, a tablet, a granule, a powder, a syrup, an emulsion, a suppository, an ointment, an eyedrop, a nosedrop, a troche, an aerosol, an injection, etc.
  • a liquid preparation suited for oral administration for example, an emulsion and a syrup can be prepared using water; sugars such as sucrose, sorbitol, fructose, etc.; glycols such as polyethylene glycol, propylene glycol, etc.; oils such as sesame oil, olive oil, soybean oil, etc.; antiseptics such as a p-hydroxybenzoic acid ester, etc.; flavors such as strawberry flavor, pepper mint, etc. Further a capsule, a tablet, a powder and a granule, etc.
  • an excipient such as lactose, glucose, sucrose, mannitol, etc.; a disintegrator such as starch, sodium alginate, etc.; a lubricant such as magnesium stearate, talc, etc.; a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, etc.; a surfactant such as an aliphatic ester, etc.; a plasticizer such as glycerine, etc.
  • an excipient such as lactose, glucose, sucrose, mannitol, etc.
  • a disintegrator such as starch, sodium alginate, etc.
  • a lubricant such as magnesium stearate, talc, etc.
  • a binder such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, etc.
  • a surfactant such as an aliphatic ester, etc.
  • a plasticizer such as glycerine, etc.
  • a preparation suited for parenteral administration is composed of a sterile aqueous preparation containing, active compounds which are preferably isotonic to the blood of the recipient.
  • a solution for injection is prepared using carriers composed of a saline solution, a glucose solution or a mixture of saline water and glucose solution.
  • a nasal spray preparation is composed of a purified aqueous solution of the active compounds which contains an antiseptic and an isotonic agent. Such a preparation is adjusted to pH compatible with the nasal membrane and to an isotonic state.
  • An ocular preparation is prepared in a manner similar to the nasal spray, except that pH and isotonic factors are controlled so as to fit those of eyes.
  • a topical preparation is prepared by dissolving or suspending the active compound in one or more media, for example, a mineral oil, petroleum, a polyvalent alcohol or other bases used for topical medical preparations.
  • media for example, a mineral oil, petroleum, a polyvalent alcohol or other bases used for topical medical preparations.
  • a preparation for rectal administration is provided as a suppository using conventional carriers, for example, cacao fat, hydrogenated fat or hydrogenated fat carboxylic acid, etc.
  • parenteral preparations may also be added with one or more auxiliary components such as a diluent, a fragrance, an antiseptic (including an antioxidant), an excipient, a disintegrator, a lubricant, a binder, a surfactant, a plasticizer and the like.
  • auxiliary components such as a diluent, a fragrance, an antiseptic (including an antioxidant), an excipient, a disintegrator, a lubricant, a binder, a surfactant, a plasticizer and the like.
  • Effective dose and regimen of administration of Compound (I) or pharmaceutically acceptable salts thereof vary depending upon mode of administration, age and body weight of the patient and properties or severity of conditions to be treated. In which may be administered as a single or divided doses.
  • E-form compound, 21.5 g, isolated from the Z/E mixture described above in a conventional manner and 23.5 g of sodium acetate were suspended in 250 ml of dichloroethane and, 27.1 ml of ethyl chloroformate was dropwise added to the suspension. After completion of the dropwise addition, the mixture was stirred at room temperature for an hour and the solvent was distilled off under reduced pressure. The residue was extracted with 400 ml of ethyl acetate. After washing with saturated sodium chloride aqueous solution and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from isopropanol to give 14.3 g of the objective compound as white crystals.
  • the objective compound was obtained as colorless oil from Compound f obtained in Reference Example 6 in a manner similar to Reference Example 2.
  • the objective compound was obtained as colorless oil in a manner similar to Reference Example 8 using Compound g obtained in Reference Example 7.
  • the objective compound was obtained as colorless oil in a manner similar to Reference Example 9 using Compound l obtained in Reference Example 12.
  • the objective compound was obtained as colorless oil in a manner similar to Reference Example 10 using Compound m obtained in Reference Example 13.
  • the objective compound was obtained as colorless oil from Compound c (E-form) obtained in Reference Example 3 in a manner similar to Reference Example 11.
  • the aforesaid product, 3.5 g, showing an E/Z ratio of about 1:1 was dissolved in 50 ml of pyridine and 1.7 ml of methanesulfonyl chloride was dropwise added under ice cooling. After stirring for an hour under ice cooling, the solvent was distilled off under reduced pressure. The residue was extracted with 200 ml of ethyl acetate. The extract was washed in succession with 1N hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give 4.3 g of the objective compound as colorless oil.
  • This product was provided for use in the following reaction step without particular purification.
  • a ratio of E/Z was about 1:1.
  • the objective compound was obtained as colorless oil in a manner similar to Reference Example 11, using Compound j obtained in Reference Example 10 and homopiperazine.
  • Example 15 the objective compound was prepared using the corresponding starting material n, p or r and 4-benzylpiperidine in a manner similar to Example 1.
  • the objective compound was prepared using Compound t obtained in Reference Example 20 and 4-benzylpiperidine in a manner similar to Example 1. A ratio of E/Z was 1:1.
  • Example 19 the objective compound was prepared using the corresponding starting material c or e and the corresponding piperazine or piperidine compound in a manner similar to Example 1.
  • the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to EXAMPLE 23.
  • the objective compound was prepared by hydrolyzing Compound 47a obtained in Example 10 in a manner similar to Example 23.
  • Example 34 the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
  • Example 16 Compound 101a, 0.33 g, obtained in Example 16 was hydrolyzed in a manner similar to Example 23 to give 0.3 g of the corresponding Compound 101b.
  • This compound was dissolved in 50 ml of acetone and 80 mg of fumaric acid was added to the solution followed by stirring at room temperature for 2 hours. The solvent was distilled off under reduced pressure. The resulting crude product was recrystallized from isopropanol to prepare 0.14 g of the objective compound.
  • the objective compound was prepared using Compound 103a obtained in Example 17 in a manner similar to Example 39.
  • the objective compound was prepared by hydrolyzing Compound E/Z-85a obtained in Example 18 in a manner similar to Example 23.
  • a ratio of E/Z was 38:62.
  • Example 42 the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
  • a ratio of E/Z was 85:15.
  • Example 21 Compound E-96a, 2.0 g, obtained in Example 21 was hydrolyzed in a manner similar to Example 23 to give 1.7 g of the corresponding Compound E-96b.
  • This compound was dissolved in 200 ml of acetone and 0.43 g of fumaric acid was added to the solution followed by stirring at room temperature for an hour. The precipitated crystals were taken by filtration to give 1.5 g of the objective compound.
  • the objective compound was prepared by hydrolyzing Compound E-98a obtained in Example 22 in a manner similar to Example 23.
  • Example 45 Compound E-98b' obtained in Example 45 was converted into the sodium salt in a manner similar to Example 31.
  • the objective compound was prepared using Compound s obtained in Reference Example 19 and cinnamyl bromide in a manner similar to Example 47.
  • the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives and then converting the hydrolyzate into the fumarate in a manner similar to Example 44.
  • the crude product obtained was recrystallized from isopropyl ether to give 0.4 g of the objective compound.
  • Example 52 the objective compound was prepared using Compound k and the corresponding sulfonyl chloride compound in a manner similar to Example 51.
  • Example 54 the objective compound was prepared using Compound k and the corresponding acid chloride compound in a manner similar to Example 51.
  • the crude product obtained was solidified with isopropyl ether to give 1.6 g of the objective compound.
  • the objective compound was prepared using Compound k and benzyl chloroformate in a manner similar to Example 56.
  • Example 58 the objective compound was prepared from Compound s obtained in Reference Example 19 and the corresponding sulfonyl chloride compound in a manner similar to Example 51.
  • the objective compound was prepared using 1.4 g of Compound u obtained in Reference Example 21 and 1.0 g of 1-naphthalenesulfonyl chloride in a manner similar to Example 51.
  • Example 61 the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
  • the objective compound was prepared as the hydrochloride from Compound 27b obtained in Example 63 in a manner similar to Example 2.
  • Example 65 the objective compound was prepared by hydrolyzing esters of the corresponding oxepine derivatives in a manner similar to Example 23.
  • a tablet having the following composition is prepared in a conventional manner.
  • Powders having the following composition are prepared in a conventional manner.
  • Syrup having the following composition is prepared in a conventional manner.
  • a tablet having the following composition is prepared in a conventional manner.
  • Syrup having the following composition is prepared in a conventional manner.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
US07/281,545 1987-12-14 1988-12-08 Tricyclic thromboxane A2 antagonists Expired - Fee Related US4994463A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US07/884,208 US5302602A (en) 1987-12-14 1992-05-18 Tricyclic thromboxane A2 antagonists

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP31576987 1987-12-14
JP62-315769 1987-12-14
JP2354388 1988-02-03
JP63-23543 1988-02-03

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US07/616,095 Division US5143922A (en) 1987-12-14 1990-11-20 Tricyclic thromboxane A2 antagonists

Publications (1)

Publication Number Publication Date
US4994463A true US4994463A (en) 1991-02-19

Family

ID=26360920

Family Applications (3)

Application Number Title Priority Date Filing Date
US07/281,545 Expired - Fee Related US4994463A (en) 1987-12-14 1988-12-08 Tricyclic thromboxane A2 antagonists
US07/616,095 Expired - Fee Related US5143922A (en) 1987-12-14 1990-11-20 Tricyclic thromboxane A2 antagonists
US07/884,208 Expired - Fee Related US5302602A (en) 1987-12-14 1992-05-18 Tricyclic thromboxane A2 antagonists

Family Applications After (2)

Application Number Title Priority Date Filing Date
US07/616,095 Expired - Fee Related US5143922A (en) 1987-12-14 1990-11-20 Tricyclic thromboxane A2 antagonists
US07/884,208 Expired - Fee Related US5302602A (en) 1987-12-14 1992-05-18 Tricyclic thromboxane A2 antagonists

Country Status (5)

Country Link
US (3) US4994463A (fr)
EP (1) EP0325755B1 (fr)
AU (1) AU612437B2 (fr)
DE (1) DE3888821T2 (fr)
ES (1) ES2053692T3 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5112826A (en) * 1983-08-02 1992-05-12 Cirera Xavier D Vasodilatory dihydrodibenzocycloheptyliden-ethylpiperazine derivatives
US5302596A (en) * 1988-06-09 1994-04-12 Kyowa Hakko Kogyo Co., Ltd. Tricyclic compounds as TXA2 antagonists
WO1996031474A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Nouveaux composes heterocycliques
WO1996031503A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Nouveaux composes heterocycliques
US5952352A (en) * 1995-04-07 1999-09-14 Novo Nordisk A/S Heterocyclic compounds
US6133268A (en) * 1996-10-04 2000-10-17 Novo Nordisk A/S 1,4-disubstituted piperazines
US6323206B1 (en) 1996-07-12 2001-11-27 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US20050070549A1 (en) * 1998-09-04 2005-03-31 Luly Jay R. Chemokine receptor antagonists and methods of use thereof
US20050288319A1 (en) * 2002-11-13 2005-12-29 Carson Kenneth G CCR1 antagonists and methods of use therefor
US20070060592A1 (en) * 2001-11-21 2007-03-15 Luly Jay R Chemokine receptor antagonists and methods of use therefor

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU605501B2 (en) * 1987-08-25 1991-01-17 Kyowa Hakko Kirin Co., Ltd. Dibenz(b,e)oxepin derivative and antiallergic agent
US5703088A (en) * 1989-08-21 1997-12-30 Beth Israel Deaconess Medical Center, Inc. Topical application of spiperone or derivatives thereof for treatment of pathological conditions associated with immune responses
US5508280A (en) * 1990-05-18 1996-04-16 Merrell Pharmaceuticals, Inc. 5H-Dibenzo (A,D) cycloheptenes as muscarinic receptor antagonists
US5693645A (en) * 1992-12-23 1997-12-02 Beth Israel Deaconess Medical Center, Inc. Use of spiperone or spiperone derivatives as immunosuppressant agents
US6008213A (en) * 1995-06-29 1999-12-28 Smithkline Beecham Corporation Integrin receptor antagonists
JP3960482B2 (ja) * 1995-06-29 2007-08-15 スミスクライン・ビーチャム・コーポレイション インテグリン受容体アンタゴニスト
ZA9610736B (en) * 1995-12-22 1997-06-27 Warner Lambert Co 2-Substituted piperidine analogs and their use as subtypeselective nmda receptor antagonists
EP0920306A2 (fr) 1996-07-12 1999-06-09 Leukosite, Inc. Antagonistes des recepteurs de la chemokine et procedes d'utilisation de ces derniers
CN1099416C (zh) * 1996-12-28 2003-01-22 史密丝克莱恩比彻姆公司 整联蛋白受体拮抗剂
CO4920232A1 (es) * 1997-01-08 2000-05-29 Smithkline Beecham Corp Acidos aceticos dibenzo [a,d] cicloheptano con actividad antagonista del receptor de vitronectin
WO2004017995A1 (fr) * 2002-08-22 2004-03-04 Kyowa Hakko Kogyo Co., Ltd. Medicaments preventifs et/ou therapeutiques contre le prurit
JPWO2004017994A1 (ja) * 2002-08-22 2005-12-08 協和醗酵工業株式会社 喘息の予防および／または治療剤
WO2004093912A1 (fr) * 2003-04-23 2004-11-04 Kyowa Hakko Kogyo Co. Ltd. Agent prophylactique et/ou therapeutique contre les maladies inflammatoires a neutrophiles
WO2016100823A1 (fr) 2014-12-19 2016-06-23 The Broad Institute, Inc. Ligands du récepteur d2 de la dopamine
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
WO2023003497A1 (fr) * 2021-07-23 2023-01-26 Общество С Ограниченной Ответственностью "Валента-Интеллект" Composés ayant une action lysosomotrope et antivirale

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3354155A (en) * 1963-10-14 1967-11-21 Pfizer & Co C Aminoalkylphosphonium compounds and process for the use thereof
US3420851A (en) * 1962-12-19 1969-01-07 Pfizer & Co C Novel dibenzoxepines
JPS4830064A (fr) * 1971-08-23 1973-04-20
GB1330966A (en) * 1970-12-22 1973-09-19 Yoshitomi Pharmaceutical N-substituted piperidine compounds methods for their production and pharmaceutical compositions containing them
GB1347935A (en) * 1971-04-10 1974-02-27 Yoshitomi Pharmaceutical Piperazine derivatives methods for their production and phar maceutical compositions containing them
DE2407661A1 (de) * 1973-02-20 1974-08-29 Janssen Pharmaceutica Nv Substituierte benzimidazolinone und triazaspiro eckige klammer auf 4,5 eckige klammer zu decan-4-one, ihre salze mit saeuren, verfahren zu ihrer herstellung und arzneimittel
US4282365A (en) * 1978-11-24 1981-08-04 Merck & Co., Inc. Dibenz[b,e]oxepin compounds
EP0085870A1 (fr) * 1982-01-25 1983-08-17 Kyowa Hakko Kogyo Co., Ltd Dérivés de dibenz(b,d)oxépine et compositions pharmaceutiques les contenant
US4585788A (en) * 1973-09-06 1986-04-29 American Hoechst Corporation 6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives
US4596809A (en) * 1985-03-25 1986-06-24 Schering Corporation Substituted 1,8-naphthyridinones, useful as anti-allergic agents
JPS61152673A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
JPS61152674A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
JPS61152675A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
JPS61152676A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
EP0188802A2 (fr) * 1984-12-26 1986-07-30 Kyowa Hakko Kogyo Co., Ltd. Dérivé de dibenzo (b,e) oxépine et agent antiallergique
JPS61257981A (ja) * 1985-05-09 1986-11-15 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体および抗アレルギ−剤
EP0214779A1 (fr) * 1985-08-17 1987-03-18 The Wellcome Foundation Limited Composés tricycliques
JPS62153280A (ja) * 1985-12-25 1987-07-08 Dainippon Pharmaceut Co Ltd １，４−ジアザシクロアルカン誘導体
EP0235796A2 (fr) * 1986-03-03 1987-09-09 Kyowa Hakko Kogyo Co., Ltd. Dérivés de dibenzo[b,e]oxépine et agent anti-allergique et anti-inflammatoire
US4749703A (en) * 1984-08-10 1988-06-07 Dainippon Pharmaceutical Co., Ltd. Calcium antagonist piperazine derivatives, and compositions therefor

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4830064B1 (fr) * 1968-12-23 1973-09-17
JPS6028972A (ja) * 1983-06-29 1985-02-14 Kyowa Hakko Kogyo Co Ltd ジベンゾ［ｂ，ｅ］オキセピン誘導体
US4912222A (en) * 1988-06-17 1990-03-27 Fisons Corporation Antihistamines related to cyproheptadine

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3420851A (en) * 1962-12-19 1969-01-07 Pfizer & Co C Novel dibenzoxepines
US3354155A (en) * 1963-10-14 1967-11-21 Pfizer & Co C Aminoalkylphosphonium compounds and process for the use thereof
GB1330966A (en) * 1970-12-22 1973-09-19 Yoshitomi Pharmaceutical N-substituted piperidine compounds methods for their production and pharmaceutical compositions containing them
GB1347935A (en) * 1971-04-10 1974-02-27 Yoshitomi Pharmaceutical Piperazine derivatives methods for their production and phar maceutical compositions containing them
JPS4830064A (fr) * 1971-08-23 1973-04-20
DE2407661A1 (de) * 1973-02-20 1974-08-29 Janssen Pharmaceutica Nv Substituierte benzimidazolinone und triazaspiro eckige klammer auf 4,5 eckige klammer zu decan-4-one, ihre salze mit saeuren, verfahren zu ihrer herstellung und arzneimittel
US4585788A (en) * 1973-09-06 1986-04-29 American Hoechst Corporation 6,11-dihydrodibenz[b,e]oxepin-acetic acids and derivatives
US4282365A (en) * 1978-11-24 1981-08-04 Merck & Co., Inc. Dibenz[b,e]oxepin compounds
EP0085870A1 (fr) * 1982-01-25 1983-08-17 Kyowa Hakko Kogyo Co., Ltd Dérivés de dibenz(b,d)oxépine et compositions pharmaceutiques les contenant
US4749703A (en) * 1984-08-10 1988-06-07 Dainippon Pharmaceutical Co., Ltd. Calcium antagonist piperazine derivatives, and compositions therefor
JPS61152673A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
JPS61152674A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
JPS61152675A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
JPS61152676A (ja) * 1984-12-26 1986-07-11 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体の製造法
EP0188802A2 (fr) * 1984-12-26 1986-07-30 Kyowa Hakko Kogyo Co., Ltd. Dérivé de dibenzo (b,e) oxépine et agent antiallergique
US4596809A (en) * 1985-03-25 1986-06-24 Schering Corporation Substituted 1,8-naphthyridinones, useful as anti-allergic agents
JPS61257981A (ja) * 1985-05-09 1986-11-15 Kyowa Hakko Kogyo Co Ltd ジベンズ〔ｂ，ｅ〕オキセピン誘導体および抗アレルギ−剤
EP0214779A1 (fr) * 1985-08-17 1987-03-18 The Wellcome Foundation Limited Composés tricycliques
JPS62153280A (ja) * 1985-12-25 1987-07-08 Dainippon Pharmaceut Co Ltd １，４−ジアザシクロアルカン誘導体
EP0235796A2 (fr) * 1986-03-03 1987-09-09 Kyowa Hakko Kogyo Co., Ltd. Dérivés de dibenzo[b,e]oxépine et agent anti-allergique et anti-inflammatoire

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
Arz. Forcsh., 13, 1039, (1963). *
Arz. Forcsh., 14, 100, (1964). *
Arz.--Forcsh., 13, 1039, (1963).
Arz.--Forcsh., 14, 100, (1964).
Chem. Abs. vol. 72, 308 (1970), Abstract No. 3387d.
Chem. Abs. vol. 72, 308 (1970), Abstract No. 3387d. Columbus, Ohio, US; M. PROTIVA et al.: "Tricyclic 3-(4-phenylpiperidino)propylidene derivatives."; & Czech 128.004, 15-01-1968 *
Chem. Abs. vol. 81, 424 (1974), Abstract No. 25566z.
CHEMICAL ABSTRACTS, vol. 81, no. 5, 5th August 1974, page 424, column 1, abstract no. 25566z, Columbus, Ohio, US; & JP-A-48 030064, 17-09-73 *
Drugs, 13, 161, (1977). *
Eur. J. Med. Chem. Chimica Therapeutica, P. Dostert et al., Compos s Tricycliques Portant une Cha ne Alkylaminoalkylthio. Synth se et Activit Pharmacologique, May Jun. 1974 9, No. 3, p. 259. *
Eur. J. Med. Chem.--Chimica Therapeutica, P. Dostert et al., "Composes Tricycliques Portant une Chaine Alkylaminoalkylthio. Synthese et Activite Pharmacologique," May-Jun. 1974-9, No. 3, p. 259.
J. Med. Chem. 19, 941, (1976). *
J. Med. Chem. 20, 1499, (1977). *
J. Med. Chem. 21, 633, (1978). *
J. Med. Chem., M. Cerelli et al., Antiinflammatory and Aldose Reductase Inhibitory Activity of Some Tricyclic Arylacetic Acids, vol. 29, 2347, (1986). *

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5112826A (en) * 1983-08-02 1992-05-12 Cirera Xavier D Vasodilatory dihydrodibenzocycloheptyliden-ethylpiperazine derivatives
US5302596A (en) * 1988-06-09 1994-04-12 Kyowa Hakko Kogyo Co., Ltd. Tricyclic compounds as TXA2 antagonists
US5952352A (en) * 1995-04-07 1999-09-14 Novo Nordisk A/S Heterocyclic compounds
WO1996031503A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Nouveaux composes heterocycliques
WO1996031474A1 (fr) * 1995-04-07 1996-10-10 Novo Nordisk A/S Nouveaux composes heterocycliques
US6323206B1 (en) 1996-07-12 2001-11-27 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6133268A (en) * 1996-10-04 2000-10-17 Novo Nordisk A/S 1,4-disubstituted piperazines
US6329385B1 (en) 1998-01-21 2001-12-11 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6433165B1 (en) 1998-01-21 2002-08-13 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6509346B2 (en) 1998-01-21 2003-01-21 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US6613905B1 (en) 1998-01-21 2003-09-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US20050070549A1 (en) * 1998-09-04 2005-03-31 Luly Jay R. Chemokine receptor antagonists and methods of use thereof
US7271176B2 (en) 1998-09-04 2007-09-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US8058287B2 (en) 2001-11-21 2011-11-15 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US20070060592A1 (en) * 2001-11-21 2007-03-15 Luly Jay R Chemokine receptor antagonists and methods of use therefor
US9663537B2 (en) 2001-11-21 2017-05-30 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use
US7541365B2 (en) 2001-11-21 2009-06-02 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use therefor
US20090281081A1 (en) * 2001-11-21 2009-11-12 Luly Jay R Chemokine receptor antagonists and methods of use therefor
US8653096B2 (en) 2001-11-21 2014-02-18 Millennium Pharmaceuticals, Inc. Chemokine receptor antagonists and methods of use thereof
US20050288319A1 (en) * 2002-11-13 2005-12-29 Carson Kenneth G CCR1 antagonists and methods of use therefor
US7977350B2 (en) 2002-11-13 2011-07-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US20110230516A1 (en) * 2002-11-13 2011-09-22 Carson Kenneth G CCR1 Antagonists and Methods of Use Therefor
US20100249174A1 (en) * 2002-11-13 2010-09-30 Carson Kenneth G Ccr1 antagonists and methods of use therefor
US8394817B2 (en) 2002-11-13 2013-03-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US7732459B2 (en) 2002-11-13 2010-06-08 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor
US9334283B2 (en) 2002-11-13 2016-05-10 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use thereof
US20080139602A1 (en) * 2002-11-13 2008-06-12 Millennium Pharmaceuticals, Inc. CCR1 antagonists and methods of use therefor

Also Published As

Publication number Publication date
EP0325755B1 (fr) 1994-03-30
AU612437B2 (en) 1991-07-11
EP0325755A1 (fr) 1989-08-02
DE3888821D1 (de) 1994-05-05
DE3888821T2 (de) 1994-08-11
ES2053692T3 (es) 1994-08-01
AU2671188A (en) 1989-06-15
US5302602A (en) 1994-04-12
US5143922A (en) 1992-09-01

Similar Documents

Publication Publication Date Title
US4994463A (en) Tricyclic thromboxane A2 antagonists
EP0345747B1 (fr) Composés tricycliques
US5010087A (en) Tricyclic compounds and TXA2 antagonistic compositions thereof
US5116863A (en) Dibenz[b,e]oxepin derivative and pharmaceutical compositions thereof
WO1993014084A2 (fr) Derives de piperidine
US5242931A (en) Tricyclic compounds as TXA2 antagonists
HU207311B (en) Process for producing chromane derivatives and pharmaceutical compositions containing them
NO860319L (no) Fremgangsmaate for fremstillig av terapeutisk aktive 4h-1-benzopyran-4-on-derivater og deres svovelholdige analoger.
FR2618437A1 (fr) Nouveaux derives du benzopyranne, leur preparation et les medicaments qui les contiennent
US5089505A (en) 1-arylethyl-3-substituted piperidines
NO170082B (no) Analogifremgangsmaate for fremstilling av terapeutisk aktive benzothiazinderivater
NO803453L (no) Fremgangsmaate ved fremstilling av piperidylbenzimidazolonderivater
JPS6140674B2 (fr)
US4356186A (en) Acetic acid derivatives and composition containing the same
Oshima et al. Tricyclic thromboxane A 2 antagonists
US5057514A (en) Compounds effective as cerebral schemia treating agents
US5179092A (en) Compound effective as cerebral insufficiency improver
JPH07100688B2 (ja) 環状アミン誘導体
US5292768A (en) Compound effective as cerebral insufficiency improver
US3464983A (en) 4h-benzo(4,5)cyclohepta(1,2-b)thiophenes
US5081152A (en) Azulene derivatives as thromboxane a2 and prostaglandin endoperoxide receptor antagonist
JP3162175B2 (ja) クロマン誘導体若しくはジヒドロベンゾフラン誘導体
JPH01308274A (ja) 三環式化合物
US5534626A (en) 1-arylethyl-3-substituted piperidines
US5308863A (en) Substituted aromatic sulfonamides as antiglaucoma agents

Legal Events

Date Code Title Description
AS Assignment

Owner name: KYOWA HAKKO KOGYO CO., LTD., 6-1, OHTEMACHI ITCHOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNORS:OSHIMA, ETSUO;OBASE, HIROYUKI;KARASAWA, AKIRA;AND OTHERS;REEL/FRAME:004986/0299

Effective date: 19881128

Owner name: KYOWA HAKKO KOGYO CO., LTD., A CORP. OF JAPAN, JAP

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:OSHIMA, ETSUO;OBASE, HIROYUKI;KARASAWA, AKIRA;AND OTHERS;REEL/FRAME:004986/0299

Effective date: 19881128

CC Certificate of correction
FPAY Fee payment

Year of fee payment: 4

REMI Maintenance fee reminder mailed
LAPS Lapse for failure to pay maintenance fees
FP Lapsed due to failure to pay maintenance fee

Effective date: 19990219

STCH Information on status: patent discontinuation

Free format text: PATENT EXPIRED DUE TO NONPAYMENT OF MAINTENANCE FEES UNDER 37 CFR 1.362